Community Research and Development Information Service - CORDIS



Project ID: 616088
Funded under: FP7-IDEAS-ERC
Country: Israel

Periodic Report Summary 3 - SPERMDESTRUCT (Cellular Destruction Mechanisms that Create New Lives)

A key discovery in the field of programmed cell death (PCD) is the realization that apoptosis, the most abundant form of PCD in metazoa, is executed by an evolutionary conserved family of proteases called caspases. Since then, the combined efforts of many research groups have led to a deep understanding of how caspases are activated and regulated during apoptosis. However, a constantly growing body of research indicates that caspase activation may not necessarily lead to cell death. To date, more than 50 caspase-dependent non-lethal cellular processes (CDPs) have been described in a variety of tissues and organisms. On the other hand, there is emerging evidence suggesting that cell death in metazoa can sometimes proceed in the absence of caspases by triggering alternative cell death (ACD) pathways. The Drosophila sperm system serves as an excellent paradigm to study both CDPs and ACDs, as we discovered that about 25% of the pre-meiotic male germ cells are constantly eliminated through a caspase-independent cell death pathway, while during spermatid terminal differentiation, caspases promote the removal of the spermatid bulk cytoplasmic contents. Furthermore, after fertilization, the paternal mitochondria is eliminated by mechanisms originated in the egg, thus also constituting a paradigm to study organelle-specific destruction.

Thus far, we have made significant progress towards addressing several key questions related to the different cellular destruction processes that are associated with the lifecycle of the fly sperm. Furthermore, our work has generated two new paradigms of CDPs and ACDs. In short, we identified the Hippo/Warts pathway in the cyst somatic cells (which encapsulate the developing germ cells throughout spermatogenesis) as an important inducer of the caspase-independent germ cell death program, indicating that the decision for the germ cells to die is taken by the associated somatic cells. This work has also led to the discovery of another physiological ACD paradigm, in which the lysosomal pathway is also dominant, uncovering a surprising mechanism of lysosomal-dependent cell death. We were also successful in revealing the mechanism by which terminally differentiating spermatids’ mitochondria limit the rate of caspase activation to prevent excessive activation and unwanted cell death. This work also identified an intriguing moonlighting role of a Krebs cycle enzyme subunit on the mitochondrial surface. Furthermore, in the course of investigating this caspase-dependent non-lethal cellular process, we also uncovered a new phenomenon and another (important) non-lethal role of caspases, not in promoting cell differentiation, but rather in maintaining tissue integrity. This finding is particularly exciting, as it demonstrates a caretaker role of caspases at their basal/low levels, which are far below the threshold required to induce apoptosis. Our work on the destruction of the paternal mitochondria after fertilization identified unique MVB-like vesicles which originate in the egg and are essential for the recognition and destruction of the sperm mitochondria. Furthermore, we now identified the major ubiquitin E3 ligases and a major mitochondrial ubiquitinated substrate that are involved in this process. Finally, we have recently started performing whole exome sequencing of blood samples from infertile male patients with malfunction of late spermatogenesis, in order to identify the causing mutations, and whether they are related to the Drosophila spermatogenesis processes that we are investigating. We are expecting to achieve almost all of the goals presented in the ERC proposal by the end of the grant period, as well as have two new exciting paradigms to continue exploring key questions related to CDPs and ACDs, and the possible evolutionary origin of caspases in metazoa.

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